Neurodegenerative diseases are debilitating and incurable condition resulting in the progressive degeneration of nerve cells which causes problems with movement or mental functioning. Alzheimer's disease is the most common form of dementia and an irreversible neurodegenerative disorder. The mechanism of Alzheimer's disease is still unknown. The changes in the primary DNA sequence due to heritable alterations in the gene are known as epigenetics. The most studied epigenetic mechanisms are DNA methylation, histone modifications, and noncoding RNAs. Therefore, this change triggers the alterations in the transcriptional level of genes which are involved in the pathogenesis of Alzheimer's disease. Over the past decade, it is progressively clear that the epigenetic mechanisms play an important role in the pathogenesis of Alzheimer's disease. The literature search was performed on reviews addressing the topics in the databases PubMed and Google Scholar. This review focuses on the three major epigenetic mechanisms and their role in the pathogenesis of Alzheimer's disease.

Neurodegenerative diseases are a heterogeneous group of disorders characterized by the progressive degeneration in the central and peripheral nervous system (https://www.nature.com/subjects/neurodegenerative-diseases). Alzheimer's disease is the most common form of dementia characterized by the impaired cognitive abilities; severe memory loss caused by the aggregations of two kinds of proteins, namely, amyloid plaques and neurofibrillary tangles are the primary markers of Alzheimer's disease where the neuronal loss in the hippocampus and neocortex regions.[1],[2] Amyloid plaques are the aggregation of the amyloid precursor proteins (APPs) which amyloid-beta peptides cleaved from the APP by β and γ secretase. Similarly, neurofibrillary tangles are the aggregates of tau proteins which are phosphorylated. These two proteins are the hallmarks in the development of Alzheimer's disease. Although there are many genetic links in the Alzheimer's disease cases, most of the people do not show those genetic imprints; thus, there is a consideration for series of nongenetic imprints.[3] Of all Alzheimer's disease cases, it is estimated that one-half of the cases show heritability in Alzheimer's disease,[4] while the other two-third Alzheimer's disease cases show the nonhereditary aspects which include the epigenetic mechanisms underlying blood sugar levels, blood pressure, overweight, and depression.[5] The core mechanism of Alzheimer's disease is still not fully understood. In the recent years, an epigenetic change plays a major role in the mechanism of Alzheimer's disease. Epigenetics are the study of heritable changes in gene function that occur independently of alterations to primary DNA sequence.[6] The most studied epigenetic mechanisms are DNA methylation, histone modifications, and noncoding RNAs (ncRNAs). Therefore, this change triggers the alterations in the transcriptional level of genes which are involved in the pathogenesis of Alzheimer's disease. Over the past decade, it is progressively clear that the epigenetic mechanisms play an important role in the pathogenesis of Alzheimer's disease. This review focuses on describing about the three major epigenetic mechanisms and their role in Alzheimer's disease pathogenesis.

Search Methods

The literature search was performed on reviews addressing the topics below in the databases PubMed and Google Scholar. Some literature was searched through Google. The search terms (concept) included the following topics: (1) Alzheimer's Disease, (2) epigenetics, and (3) role of epigenetics in Alzheimer's disease. The search language was English. There was no specific time limit.

Epigenetics and Alzheimer's Disease

Alzheimer disease pathology is caused by genetic alterations in the genes such as APP, presenilin 1, 2, and apolipoprotein E along with environmental factors such as chemical exposure, lifestyle changes, injury to the brain by external force long with the epigenetic changes such as the disruption in the enzyme activity, which are involved in DNA methylation and histone modifications and genetic modifications cause alterations in the phenotypic expressions, leading to the Alzheimer's disease pathology.[7]

Epigenetic Modifications

DNA methylation

DNA methylation is an important biochemical process in the higher organisms for normal development, which involves the accumulation of methyl group in the 5' of the cytosine within the CpG dinucleotides. This accumulation is enhanced by DNA methyltransferases (DNMTs), which is heritable.[8]

These CpG dinucleotides are more concentrated in the regions called CpG islands located in the promoter regions. During the methylation process, it directly affects the transcriptional binding factors and also it suppresses the expression of the gene.[9] Currently, a new DNA methylation mechanism has been reported in which the 5' methylcytosines are oxidized by forming 5' hydroxymethylcytosine,[10] thereby inhibiting the DNA interaction with the DNA-binding proteins to a 5' methylcytosines.[11]

The SH-SY5Y, neuronal-like cell lines are treated with conditioned media, showed a mutation Indiana (V717F) with amyloid beta peptides at higher concentration.[12],[13] The DNA microarray analysis of IMR-32 neuroblastoma cell lines, which were treated with higher levels of synthetic amyloid beta peptides, does not show any DNA methylation alterations at significant levels.[14] Similarly, the DNA methylation is seen in the brain regions' entorhinal cortex and hippocampus of Alzheimer's patients using antibodies that recognize methylated DNA.[15],[16] However, an opposite result was noted in the studies using the same method they reported that no differences were seen in the brain regions such as entorhinal cortex, frontal cortex, temporal cortex, and the hippocampus.[17],[18],[19] Hypomethylation within two distinct promoter regions of the CRTC1 gene was decreased in human hippocampus affected by Alzheimer's subjects compared with controls and methylation within prom1 showed a strong inverse correlation with p-tau deposition.[20]

In Alzheimer's disease cases, the DNA methylation and DNA hydroxymethylation are seen in the certain regions of the genome; this is due to the abnormal epigenetic mechanism of CpG island initiates the pathologic alteration in Alzheimer's disease.[21],[22] Highlighted that there is an increase in DNA hydroxymethylation levels in Alzheimer's disease subjects compared to age-matched controls. DNA methylation in the promoter region decreases the extended regions of cytosine and guanine repeats in the mammalian genes. These sites are heavily targeted by DNMTs and are known to modulate gene expression.[23]

In the J20 mouse model, an age-related decrease in DNA methylation was found in the dentate gyrus, and a decrease in the ratio between DNA methylation and hydroxymethylation was found in the dentate gyrus and cornu ammonis 3 also; only the J20 model showed an age-related reduction in global DNA methylation, while DNA hypermethylation was observed in the 3xTg-Alzheimer's disease model.[24]

Histone modifications

Histone acetylation is a process in which acetyl coenzyme A transfers acetyl to the lysine residues of core histone N terminal domains catalyzed by histone acetyltransferases (HATs); the acetylation process not only equalizes the positive charge in the histone and also lowers the attraction of histone with phosphate in DNA, which is negatively charged. Hence, it triggers the gene transcription process by losing the chromatin structure.[25]

Various posttranslation modifications such as histone acetylation, methylation, phosphorylation, ubiquitination, and sumoylation are seen in the histones; these modifications are mostly seen in the N-terminal tails of histones (H2A, 2B, H3, and H4) not only protruding from the surface of the nucleosome but also on its core region. These modifications alter the histone code, an epigenetic change involved in various pathological phenomena. In general, histone acetylation, especially at H3 and H4 lysine residues, correlates with transcriptional activity, while histone deacetylation and methylation inhibit gene expression.[26] Studies on histone modifications are very fewer when compared with DNA methylation particularly in Alzheimer's disease.

Peleg et al.[27] in their study with 16-year-old mouse proved experimentally that the learning and memory process reported that the decreased H4K12 acetylation level, in turn, affects the hippocampus region which is concerned for memory; this decreased acetylation level is due to the inhibition of HATs gene but a histone deacetylase inhibitor called suberoylanilide hydroxamic acid can elevate the levels of histone H4 at lysine 18. Guan et al.[28] investigated about the histone deacetylase expression in the mouse, it is noted that the overexpression of histone deacetylase 2 lowers the density of dendritic spine, number of synapses as well as the memory. A significant increase in the levels of histone deacetylase 6, a modulator for tau phosphorylation and accumulation, has been seen in the brain regions such as cerebral cortical and hippocampus tissues in Alzheimer's disease patients when compared with the control subjects.[29] Similarly, the elevated levels of phosphorylated H2AX at Ser139 are seen in the hippocampus astrocytes of Alzheimer's subjects.[30]

Gupta et al.[31] reported that the suppression of histone deacetylase with sodium butyrate results in elevated levels of H3K4 trimethylation and lowered levels of H3K9 demethylation in the hippocampus regions of the brain. The in vivo and in vitro studies and in Alzheimer's subjects show a significant increase in the levels of histone deacetylase II leads to the transcriptions of memory and learning-related genes. The changes in the inhibition factor of histone deacteylase II could regenerate the neuronal and synaptic structure so that it improves the cognitive impairments.[29] Similarly, the genome-wide patterns of lysine H3K27 acetylation H3K27ac showed a strong mark of active enhancers and promoters with gene expression and transcription factor binding in the brain entorhinal cortex samples from Alzheimer's subject than the control cases using chromatin immunoprecipitation, followed by highly parallel sequencing.[32]

Zhang et al.[33] in his investigation reported that, when compared with aged controls of the Alzheimer's subjects showed decreased level of histone acetylation in the temporal lobes of the brain regions. However, Naryan et al.[34] in his study on the levels of histone acetylation levels from the postmortem brains of Alzheimer's disease concluded that acetylation level is higher in the brains of Alzheimer's patients. It is noted that the excess of amyloid beta peptides plays a role in histone regulation. In the Tg2576 mice, histone H3 acetylation and phosphorylation is increased in prefrontal cortex, and histone H3 methylation was also observed increased in prefrontal cortex but decreased in the striatum, while histone H4 acetylation in the CA1 of the hippocampus is higher.[35]

In the process of amyloid precursor protein hydrolysis into amyloid beta peptide, APP intracellular C-terminal domain (AICD) will also be generated.[36] With the transcription of histone acetylation-regulatory genes, AICD, Fe65, and Tip60 (HAT) can form into trimetric complexes. The Alzheimer's disease-related genes including APP, glycogen synthase kinase 3 beta, β-site of APP cleaving enzyme 1, and neprilysin are synchronized by the AICD-Fe65 complex. This AICD-Fe65 complex is involved in managing of APP. The overexpression of Fe65 will generate more amyloid beta peptides and promote the occurrence and development of Alzheimer's disease.[37]

Noncoding RNAs

The noncoding sequences are mostly transcribed into different forms of ncRNA including micro RNAs. The microRNAs are a group of noncoding RNAs that regulate the repression of translated messenger RNAs in a specific sequence. Most of the microRNAs seen in the brain is important for functioning the neuronal and glial development, followed by the differentiation, proliferation, and metabolism.[38]

Aggregation of these microRNAs causes the de-regulation of the genes in the brain and plays an important role in the Alzheimer's disease.[39] Recent profiling research in human or mouse models suggests that miRNAs are aberrantly expressed in Alzheimer's disease and it has more implications in the amyloid beta, tau, inflammation, and cell death which are the core path mechanisms in the Alzheimer's disease. In addition, regulation of miRNAs varies in blood, and cerebral spinal fluid may indicate alterations in Alzheimer's disease. Together with brain-specific miRNAs, these miRNAs could be potential biomarkers for Alzheimer's disease.[40] APP has been studied in the microRNAs target gene, and in the in vitro studies, most of the several micro RNAs have been demonstrated to regulate the APP messenger RNA, such as miRNAlet-7,[36] the miR-20a family including miRs 20a, miRs 17, and miRs 106b,[37],[39] miRs 106a and miRs 520c,[41] miRs 101,[42] and miRs 16.[43] In controversially, that some studies have shown that miR-106a, miR-106b, and miR-520c are not linked with APP expression in Alzheimer's disease.[44] In their mouse model downregulated, mi-101 is seen in temporal and parietal cortex, and also it was more concentrated in the anterior temporal cortex of the brain regions, but both the factors such as inhibiting and overexpression of mi-101 significantly lowers the APP, leading to the accumulation of beta amyloids in hippocampus neurons.

Liu et al.[45] in his in vitro and in vivo analysis of miR-16 showed that APP has a major role to alter the Alzheimer's-associated pathogenesis in Alzheimer's mice and overexpression in miR-16 leads to condensed APP expression. Further pathological studies in the Alzheimer's patients have shown that miR-106b was decreased in the cerebral cortex and did not show any correlation between the levels of miR-20a, miR-17–5p, and miR-106b with the concentration of APP in the cerebral cortex.[46]

The levels of β-secretase-1-related miR-107 and miR-29a/b are decreased and the effect of this is lowered in the Alzheimer's affected subjects. The studies in the Alzheimer's patients have shown that the overexpression of miR-34a inversely alters the expression of synaptic targets which includes synaptotagmin-1 and syntaxin-1A.[47] Long and Lahiri[48] investigated the human brain samples with moderated Alzheimer's showed reduced miR-153 levels and these results indicate that the decreased levels of miR-153 increase the APP expression. Lehmann et al.[49] demonstrated that miRNAs like Let-7 may play a role as a transmitter and TLR7 as an important element which is seen in the central nervous pattern dent in the Alzheimer's disease.

In the nervous system, the expression of long-chain ncRNA can be seen under normal physiologic conditions and in disease states. Some long-chain ncRNA regulates brain development and synaptic plasticity. In Alzheimer's disease, several long-chain ncRNAs have been demonstrated to regulate β-amyloid production/generation, synaptic impairment, neurotrophin depletion, inflammation, mitochondrial dysfunction, and stress responses.[50]

The long-chain ncRNA can regulate gene expression with regard to different aspects, such as epigenetic regulation, transcription regulation, and posttranscriptional regulation, which is involved in the pathogenesis of many complex diseases including Alzheimer's disease. These results suggest that microRNAs may play an important role in cytoskeleton pathology in Alzheimer's disease.[51],[52] A first study to study about the dysregulation in the hippocampal expression patterns in the long-chain ncRNA rat model of Alzheimer's disease and also to demonstrate the involvement of different lncRNA expression patterns in the hippocampal pathogenesis of Alzheimer's disease out of 315 long-chain ncRNA around 311 showed significant dysregulation in the Alzheimer's disease model and the expression were validated using real-time polymerase chain reaction.

Conclusion

There are diverse epigenetic alterations in which they are interrelated with each other and leads to the pathogenesis of Alzheimer's disease. The important contribution of epigenetic modifications in Alzheimer's is nothing, but it helps in the earlier identification and detection of Alzheimer's disease such that the worsening of the disease can be prevented and also treated for its future therapeutic value.